Multiple myeloma (MM) is a malignancy with poor survival and without known modifiable risk factors. Thus, prospective studies are needed to characterize the etiology of MM to inform the development of prevention strategies. Laboratory research has described important roles for the IGF-1 and IL-6 pathways in MM pathogenesis. With a collaborative study that includes a total of at least 498 MM cases and 996 controls with prospectively collected biospecimens, we are uniquely situated to conduct the first examination of the role of IGF-1 and IL-6 in MM etiology. This application addresses the following specific hypotheses: 1. Insulin-like growth factor (IGF)-1 pathway a. Circulating levels of IGF-1, IGF binding protein (IGFBP)-1, IGFBP-3, acid labile subunit (ALS), and C- peptide are related to increased incidence of MM b. Specific polymorphisms and haplotypes in the IGF-I, IGFBP-1,-2, and -3, IGF-I receptor (IGF-IR), and insulin receptor substrate (IRS)-1 and -2 genes are associated with increased risk of MM 2. Interleukin (IL)-6 upregulation and B-cell stimulation a. Plasma levels of IL-6, slL-6R, and C-reactive protein are positively associated with MM. b. Specific polymorphisms and haplotypes in the IL-6 pathway increase risk of MM. We will conduct pooled prospective studies with incident cases of MM from nine large cohorts with archived, prospectively acquired plasma and DNA specimens: the Women's Health Initiative, the Nurses'Health Study, the Health Professionals'Follow-up Study, the Women's Health Study, the Physician's Health Study, and the Singapore Chinese Cohort. From the intramural program at NCI, we have PLCO and ATBC and from Australia, we have the Melbourne Collaborative Cohort. We will utilize a prospective nested case- control design to examine the associations of the serologic and genetic biomarkers with incident MM. In secondary analyses, we will explore whether the association of a given IGF-1- or IL-6-related marker with MM varies by status of known or suggested risk factors, including age, gender, MGUS status, or body mass index. Each cohort is represented by a senior investigator (or study PI) who will oversee the case-control identification from that study, and then participate in the planning and interpretation of data analyses. The team is led from by Drs. Colditz and Anderson and is supported by a senior statistician (Dr. Rosner) and a study director (Dr. Birmann) who is funded, in part, through a K award.